Modeling of large-scale hoxbb cluster deletions in zebrafish uncovers a role for segmentation pathways in atrioventricular boundary specification

Peinan Hu; Bingqi Wang; Dongxu Jin; Yedan Gu; Hongyang He; Xiangli Meng; Wandi Zhu; David Y Chiang; Weiming Li; Calum A MacRae; Yao Zu

doi:10.1007/s00018-023-04933-2

Modeling of large-scale hoxbb cluster deletions in zebrafish uncovers a role for segmentation pathways in atrioventricular boundary specification

Cell Mol Life Sci. 2023 Oct 6;80(11):317. doi: 10.1007/s00018-023-04933-2.

Authors

Peinan Hu^#^{1

2}, Bingqi Wang^#^{1

2}, Dongxu Jin^#^{1

2}, Yedan Gu^{1

2}, Hongyang He^{1

2}, Xiangli Meng^{1

2}, Wandi Zhu³, David Y Chiang³, Weiming Li⁴, Calum A MacRae⁵, Yao Zu^{6

7

8}

Affiliations

¹ International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, 201306, China.
² Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China.
³ Cardiovascular Medicine Division, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, 02115, USA.
⁴ Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI, 48824, USA.
⁵ Cardiovascular Medicine Division, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, 02115, USA. cmacrae@bwh.harvard.edu.
⁶ International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, 201306, China. yzu@shou.edu.cn.
⁷ Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China. yzu@shou.edu.cn.
⁸ Cardiovascular Medicine Division, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, 02115, USA. yzu@shou.edu.cn.

^# Contributed equally.

PMID: 37801106
DOI: 10.1007/s00018-023-04933-2

Abstract

Hox genes orchestrate the segmental specification of the muscular circulatory system in invertebrates but it has not proven straightforward to decipher segmental parallels in the vertebrate heart. Recently, patients with HOXB gene cluster deletion were found to exhibit abnormalities including atrioventricular canal defects. Using CRISPR, we established a mutant with the orthologous hoxbb cluster deletion in zebrafish. The mutant exhibited heart failure and atrioventricular regurgitation at 5 days. Analyzing the four genes in the hoxbb cluster, isolated deletion of hoxb1b^-/- recapitulated the cardiac abnormalities, supporting hoxb1b as the causal gene. Both in situ and in vitro data indicated that hoxb1b regulates gata5 to inhibit hand2 expression and ultimately is required to pattern the vertebrate atrioventricular boundary. Together, these data reveal a role for segmental specification in vertebrate cardiac development and highlight the utility of CRISPR techniques for efficiently exploring the function of large structural genomic lesions.

Keywords: CRISPR; Heart development; Zebrafish; hoxb1b; hoxbb cluster.

MeSH terms

Animals
Gene Expression Regulation, Developmental
Heart
Humans
Transcription Factors / metabolism
Zebrafish Proteins* / genetics
Zebrafish Proteins* / metabolism
Zebrafish* / genetics
Zebrafish* / metabolism

Substances

Zebrafish Proteins
Transcription Factors

Abstract

MeSH terms

Substances

Grants and funding